Orally effective acid prodrugs of the beta-lactamase inhibitor sulbactam.
Sulbactam (1) is a beta-lactamase inhibitor with limited oral bioavailability. Lipophilic double-ester prodrug sulbactam pivoxil (2) significantly improves the oral absorption of sulbactam, as does the mutual prodrug double ester sultamicillin (3). We have found that double-ester prodrugs of sulbactam terminating in a carboxyl group (8) also were effective oral-delivery vehicles in rats. Carboxyl-terminated double esters have several potential advantages over their nonionizable lipophilic counterparts, including water solubility, crystallinity, choice of salts for dosage forms, and formation of innocuous byproducts on hydrolysis.
English
A R
AR
Pfizer Central Research, Groton, Connecticut 06340.
Girard
D
D
Jasys
V J
VJ
Martingano
R J
RJ
Kellogg
M S
MS
D000818:Animals; D001682:Biological Availability; D055598:Chemical Phenomena; D002621:Chemistry; D008297:Male; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013407:Sulbactam / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors
D011355:Prodrugs; D065093:beta-Lactamase Inhibitors; D013407:Sulbactam